SUMMARY: The FDA on November 16, 2023, approved Enzalutamide (XTANDI®) for non-metastatic Castration-Sensitive Prostate Cancer (nmCSPC) with biochemical recurrence, at high risk for metastasis. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer, and is the first treatment intervention.
The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment, and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patients with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.
Enzalutamide is a potent oral Androgen Receptor signaling inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer. The present FDA approval is based on results from the EMBARK trial.
EMBARK is a randomized, double-blind, placebo-controlled, multi-national, Phase III trial, conducted to evaluate the efficacy and safety of Enzalutamide plus Leuprolide and Enzalutamide monotherapy, as compared with Leuprolide alone, in patients with non-metastatic Hormone/Castration-Sensitive Prostate Cancer (nmHSPC or nmCSPC) prostate cancer, who have had high-risk biochemical recurrence. In this study, a total of 1068 eligible patients were randomly assigned 1:1:1 to receive Enzalutamide at 160 mg orally once daily plus Leuprolide every 12 weeks (N=355), single agent Enzalutamide at 160 mg orally once daily (N=355) or Leuprolide alone (N=358). All patients had received prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent. High risk disease was defined as a PSA doubling time of 9 months or less and a PSA level of 2 ng/ml above nadir after radiation therapy, or 1 ng/ml or more after radical prostatectomy with or without postoperative radiation therapy. The baseline characteristics were well balanced among the treatment groups. The median age was 69 years, the median PSA doubling time was 4.9 months and the median PSA level was 5.2 ng/ml. The Primary end point was Metastasis-Free Survival (MFS), as assessed by Blinded Independent Central Review (BICR) in the combination group, as compared with the Leuprolide-alone group. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first. A key Secondary end point was Metastasis-Free Survival in the Enzalutamide monotherapy group, as compared with the Leuprolide-alone group. Other Secondary end points were Patient-Reported Outcomes and Safety.
At a median follow up 60.7 months, the 5 year MFS was 87.3% in the Enzalutamide combination group and 71.4% in the Leuprolide-alone group (HR for metastasis or death 0.42; P<0.001). This represented a 58% lower risk of metastasis or death in the combination group than in the leuprolide-alone group. The 5 year MFS with Enzalutamide monotherapy versus Leuprolide alone was 80% versus 71.4% respectively (HR=0.63; P=0.005), suggesting a 37% lower risk of metastasis or death in the Enzalutamide monotherapy group than in the Leuprolide-alone group. At the time of this analysis, Overall Survival data were immature. No new safety signals were reported, and there was no substantial difference in Quality of Life measures between the treatment groups.
It was concluded that in patients with prostate cancer with high-risk biochemical recurrence, both Enzalutamide plus Leuprolide and Enzalutamide monotherapy resulted in significantly longer Metastasis-Free Survival and a longer time to PSA progression and receipt of next antineoplastic therapy, compared to Leuprolide alone, while maintaining overall Quality of Life.
Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. N Engl J Med. 2023;389:1453-1465.
